Conventional gene therapy strategies developed for used in cell-based therapy for cancer are uniformly fixed in their antigen specificity, meaning only patients fortunate enough to have the prescribed antigen expressed on the surface of their cancer cells have the potential to experience meaningful benefit. The cellular therapy field remains hindered by the inability to successfully develop the technology to deliver a flexible platform for the generation of highly personalized antigen-specific T cells with robust effector function and enhanced survival properties that can be widely applied for the treatment of the majority of patients with advanced disease. The capacity to develop a universal and flexible platform for the generation of non-MHC-restricted antigen-specific T cells has clear and significant clinical implications for adoptive immunotherapy of cancer and chronic viral infection. In this study, we propose a Biotin Binding Immune Receptor (BBIR) system that allows for the first time flexibility in targeted antigen-specificity by redirected T cells and optimized T cell survival and function in vivo. The BBIR system capitalizes on the extremely tight and specific affinity between avidin (or anti-biotin antibody) and biotin in the development of a flexible CIR platform comprised of a biotin- binding CIR (referred to as BBIR) and biotinylated human scFvs (biobodies) derived from a human scFv library. With the BBIR platform, tumor-reactive T cells are tailor-made for each patient by simply "loading" specific antigen biobodies onto autologous T cells according to the array of known antigens expressed by their tumor. Herein, this novel platform is developed, characterized and optimized for effectiveness in in vitro assay systems and in preclinical models of cancer. This flexible platform, designed to generate de novo non-MHC-restricted tumor antigen-specific T cells for adoptive immunotherapy, advances existent gene therapy technology and is well-positioned to improve the control of disease. PUBLIC HEALTH RELEVANCE: Innovative personalized approaches that broaden patient accessibility to T cell-based therapy are required to improve the control of advanced cancer and enhance health. In this study, we propose a pioneering approach to overcome the current limitations to engineered T cell therapy through the development of a universal system of T cell-based tumor targeting and killing. The public health benefit of this research will be the development of a highly personalized, "tailor-made" T cells based platform designed to broaden patient accessibility to effective T cell-based therapy of cancer.